We investigated the effect of a single ip injection of d-fenfluramine (d-fen; 5-10 mg/kg), a serotonin reuptake blocker, on cortical spreading depression (SD) in 17 male Wistar rats (300-360 g body weight). SD was elicited at the right frontal cortex by 1-min application of 2% KCl at 20-min intervals. SD propagation was monitored (electrocorticogram and DC-recording) at 2 points on the right parietal surface for 3 h. After a "baseline" recording period (1 h), d-fen was injected and the recording session was continued for 2 h. When compared to the predrug SD velocities (t = 0 min) the values measured after d-fen decreased significantly at t = 20 min (3.44 +/- 0.63 vs 2.66 +/- 0.51 mm/min; N = 17, P < 0.001), at t = 40 min (3.32 +/- 0.58 vs 2.53 +/- 0.52 mm/min; N = 14, P < 0.001), at t = 60 min (3.68 +/- 0.63 vs 2.92 +/- 0.72 mm/min; N = 11, P < 0.001) and at t = 80 min (3.57 +/- 0.61 vs 3.03 +/- 0.83 mm/min; N = 12, P < 0.05) but not at t = 100 min (3.47 +/- 0.72 vs 3.31 +/- 0.88 mm/min; N = 12) nor at t = 120 min (3.44 +/- 0.67 vs 3.37 +/- 0.76 mm/min; N = 11). Furthermore, in 19 of 48 KCl stimulations (40%) performed after d-fen in 8 rats (47%), SD velocity could not be evaluated since the phenomenon, after reaching the recording electrode nearest the stimulating point, interrupted the propagation before the second recording electrode was reached.(ABSTRACT TRUNCATED AT 250 WORDS)